Methotrexate can cause embryo-fetal toxicity, including fetal death. Use in pJIA is contraindicated
in pregnancy. Consider the benefits and risks of XATMEP and risks to the fetus when prescribing
XATMEP to a pregnant patient with a neoplastic disease. Advise females and males of reproductive
potential to use effective contraception during and after treatment with XATMEP [see Contraindications
(4), Warnings and Precautions (5.9), Use in Specific Populations (8.1, 8.3)].

INDICATIONS

Xatmep is a folate analog metabolic inhibitor indicated for the:

treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy
maintenance regimen

management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who have had
an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including
full dose non-steroidal anti-inflammatory agents (NSAIDs).

ADDITIONAL IMPORTANT SAFETY INFORMATION

Contraindications:

Xatmep is contraindicated in pregnant patients with non-malignant disease and in patients with severe
hypersensitivity to methotrexate.

Secondary malignancies can occur at all dose levels. Lymphoproliferative disease has been reported with
low-dose oral methotrexate which regressed when methotrexate is withdrawn.

Methotrexate can cause embryo-fetal toxicity and fetal death when administered during pregnancy. Consider the
risks and benefits of Xatmep and risks to the fetus when prescribing to a pregnant patient with a neoplastic
disease. Effective contraception should be practiced by patients of reproductive potential while receiving Xatmep
therapy, and for 3 and 6 months afterwards for males and females, respectively. Xatmep is contraindicated in
non-neoplastic disease.

Effects on reproduction: Methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction.
It is unknown if the infertility is reversible in affected patients.

Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially
if baseline measurements are available.

Risk of improper dosing: Once-weekly dosing is appropriate. Fatal toxicity has been reported with daily dosing.
An accurate milliliter measuring device should be used. Inform patients that a household teaspoon is not an
accurate measuring device and could lead to overdosage.

Other frequently reported reactions are malaise, fatigue, chills and fever, dizziness, and decreased resistance
to infection.

The approximate incidences of adverse reactions reported in pediatric patients with JIA treated with oral, weekly
doses of methotrexate (5 to 20 mg/m2/week or 0.1 to 0.65 mg/kg/week) were as follows (virtually all patients
were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of
corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea),
11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although
there is experience with dosing up to 30 mg/m2/week in JIA, the published data for doses above 20 mg/m2/week
are too limited to provide reliable estimates of adverse reaction rates.

Drug Interactions:

Penicillins may reduce the clearance of methotrexate; increased serum concentrations of methotrexate
with concomitant hematologic and gastrointestinal toxicity have been observed with methotrexate. Monitor
patients accordingly.